MX2012003718A - Condensed ring pyridine compounds as subtype-selective modulators of sphingosine-1-phosphate-2 (s1p2) receptors. - Google Patents

Condensed ring pyridine compounds as subtype-selective modulators of sphingosine-1-phosphate-2 (s1p2) receptors.

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MX2012003718A
MX2012003718A MX2012003718A MX2012003718A MX2012003718A MX 2012003718 A MX2012003718 A MX 2012003718A MX 2012003718 A MX2012003718 A MX 2012003718A MX 2012003718 A MX2012003718 A MX 2012003718A MX 2012003718 A MX2012003718 A MX 2012003718A
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Mexico
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isopropyl
group
alkyl
pyrazolo
dimethyl
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MX2012003718A
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Spanish (es)
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Ken Chow
Liming Wang
Wha Bin Im
Wenkui Ken Fang
Evelyn G Corpuz
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Allergan Inc
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides compounds represented by the formula I, each of which compounds may have sphingosine-1-phosphate receptor agonist and or antagonist biological activity, wherein these compounds selected from the group consisting of wherein A, B, C, D, X, Y, Z and R<sup>3</sup> are defined in the specification. Said compounds are useful for treating a disease or condition of a mammal selected from the group consisting of ocular diseases; systemic vascular barrier related diseases; allergies and other inflammatory diseases; cardiac diseases or conditions; fibrosis; pain and wounds.

Description

CONDENSED RING PYRIDINE COMPOUNDS AS SELECTIVE MODULATORS OF SUBSTITUTE FOR RECEPTORS OF SPHYNGOSINE-1-PHOSPHATE- 2 (S1P2) Field of the Invention The present invention relates to derivatives and / or sphingosine analogs which are useful as antifibrotic drugs and which are therefore useful for treating ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, fibrosis surgically induced in the cornea, conjunctiva and the Tenon capsule and for the treatment of diseases and conditions of the eye.
Background of the Invention Sphingosine is a compound that has the chemical structure indicated in the general formula described below, in which Y1 is hydrogen. It is known that several sphingolipids, which have sphingosine as a constituent, are widely distributed in the living body, including the surface of cell membranes in the nervous system.
H OH NH2 I I I H3C - (CH2) i2 - C = CH - CH - CH - CH2O - Y1 I H Ref.:229301 Sphingolipid is one of the lipids that plays an important role in the living body. The disease called lipidosis is caused by the accumulation of a specific sphingolipid in the body. Sphingolipids present on cell membranes function to regulate cell growth; participate in the development and differentiation of cells; nervous function; they are involved in the infection and malignancy of cells, etc. Many of the physiological roles of sphingolipids remain unresolved. Recently, the possibility has been indicated that ceramide, a derivative of sphingosine, plays an important role in the mechanism of cell signal transduction and studies have been carried out on its effect on apoptosis and the cell cycle.
Sphingosine-1-phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomyelin cycle (in animal cells). It has also been found in insects, yeasts and plants.
The enzyme, ceramidase, acts on ceramides to release sphingosine, which is phosphorylated by sphingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate. The reverse reaction can also occur due to the action of sphingosine phosphatases and the enzymes act in concert to control the cellular concentrations of the metabolite, whose concentrations are always low. In plasma, such concentration can reach 0.2 to 0.9 μ? and the metabolite is associated with lipoproteins, especially HDL. It should also be noted that the formation of sphingosine-l-phosphate is an essential step in the catabolism of sphingoid bases.
Like its precursors, sphingosine-l-phosphate is a very potent messenger molecule that perhaps operates singularly both intra- and intercellularly, but with functions different from those of ceramides and sphingosine. The balance between these different sphingolipid metabolites can be important for health. For example, within the cell, sphingosine-1-phosphate promotes cell division (mitosis) as opposed to cell death (apoptosis), which inhibits. Intracellularly, it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli. Current opinion seems to suggest that the balance between the levels of sphingosine-l-phosphate and ceramide and / or sphingosine in cells is critical for its viability. Like lysophospholipids, especially lysophosphatidic acid, with which it has some structural similarities, sphingosine-1-phosphate exerts many of its extracellular effects through the interaction with five specific receptors coupled to the G protein on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development and immunity and for directed cell movement.
Sphingosine-1-phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for their catabolism and is released into the bloodstream after the activation of physiological stimuli, such as growth factors, cytokines and receptor agonists. and antigens. Likewise, it can play a fundamental role in the aggregation of platelets and thrombosis and can aggravate cardiovascular disease. On the other hand, the relatively high concentration of the metabolite in high density lipoproteins (HDL) may have beneficial effects on atherogenesis. For example, there are recent indications that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic nitric oxide of the molecule. signaling by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer and there is evidence that its role in the division or Cell proliferation can have an influence on the development of cancers. These are subjects that are currently attracting great interest on the part of medical researchers and the capacity for therapeutic intervention in the metabolism of sphingosine-l-phosphate is under active investigation.
Fungi and plants have sphingolipids and the main sphingosine contained in these organisms has the formula described below. It is known that these lipids play important roles in the cell growth of fungi and plants, but the details of the roles still remain unresolved.
OH OH NH2 I I I H3C - (CH2) i2 - CH2 - CH - CH - CH - CH2OH Recently it has been discovered that the ingolipid spheric derivatives and their related compounds show a variety of biological activities through the inhibition or stimulation of metabolic pathways. These compounds include inhibitors of protein kinase C, inducers of apoptosis, immunosuppressant compounds, antifungal compounds and the like. It is expected that the substances that present these biological activities are useful compounds for various diseases.
Sphingosine derivatives have been prepared in several patents For example, see United States Patents 4,952,683; 5,110,987; 6,235,912 Bl and 6,239,297 Bl.
Also, compounds that are similar to certain sphingosine derivatives, but that have not been reported to be ligands for sphingosine receptors, have been presented in several published patents and patent applications. See, for example, U.S. Patents 5,294,722; 5,102,901; 5,403,851 and 5,580,878, the publication of the United States patent application No. 2003/0125371 A2.
Summary of the Invention The present invention provides compounds that are capable of regulating the functions of sphingolipids and pharmaceutical compositions comprising the compounds.
In one aspect of the present invention compounds that have agonist biological activity and / or sphingosine-1-phosphate receptor antagonist, represented by formula I are disclosed: where : A is a direct link or (C) and B, C and D are independently selected from the group consisting of (CR) and N, where R is H or alkyl, for example, lower alkyl; provided, however, that not all B, C and D are N and, when A is a direct link, D is (CR).
R3 is selected from the group consisting of alkyl, eg, lower alkyl: X is selected from the group consisting of 0, NR4 and CRR5, where R4 and R5 are independently selected from the group consisting of H and alkyl, eg, lower alkyl; And it is selected from the group consisting of 0 or S; Y Z is a substituted aryl ring and its pharmaceutically acceptable salts.
In a first aspect of the present invention, the ring on the left is a six-membered ring, that is, the compounds of the present invention are benzo or pyrido pyridinyl compounds. The compounds included in a first aspect of the invention can be represented by the following general formula II: where R1 and R2 are independently selected from the group consisting of H and alkyl, for example, lower alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyl radicals having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl and carboxy; R3 is selected from the group consisting of alkyl, for example, lower alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyl radicals having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl and carboxy; D is CR or N; X is 0, NR4 or CR4R5, where R4, R5 are independently selected from the group consisting of H and alkyl, for example, lower alkyl, and may have from 1 to 10 carbons and may be cyclic or branched chain alkyls having 3 to 10 carbon atoms. at 10 carbons; methoxy, hydroxyl, F, Br, I, nitrile, trifluoromethyl and carboxy; Y is 0 or S, preferably 0; Z is a substituted aryl ring, for example, a carbocyclic or heterocyclic aryl ring having the following structure: where Rs and R7 are independently selected from the group consisting of alkyl and may include from 1 to 10 carbons and may be cyclic or chain alkyls branched having from 3 to 10 carbons, alkyloxy, preferably lower alkyloxy, for example, ethyloxy, isopropyloxy, n-butyloxy; hydroxyl, halogen, preferably chlorine; nitrile, trifluoromethyl and carboxy; and E is N or CR, preferably N In a second aspect of the present invention, in the compounds of the present invention, the ring on the left is a five-membered ring, ie, the compounds are 1-H pyrazolo [4, 3-b] pyridinyl compounds. The compounds included in this second aspect of the invention can be represented by the general formula III: wherein R1, R2 and R3 are independently selected from the group consisting of H and alkyl, for example, lower alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyl radicals having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl and carboxy; R3 is selected from the group consisting of alkyl, for example, lower alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyl radicals having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl and carboxy; D is CR or N; X is O, NR 4 or CRR 5, where R 4, R 5 are independently selected from the group consisting of H and alkyl, for example, lower alkyl and may have from 1 to 10 carbons and may be cyclic or branched chain alkyls having 3 or more carbon atoms; at 10 carbons; methoxy, hydroxyl, F, Br, I, nitrile, trifluoromethyl and carboxy; Y is 0 or S, preferably O; Z is a substituted aryl ring, for example, a carbocyclic or heterocyclic aryl ring having the following structure: wherein R6 and R7 are independently selected from the group consisting of alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyls having from 3 to 10 carbons, alkyloxy, preferably lower alkyloxy, eg, ethyloxy, isopropy loxi, n-butyloxy; hydroxyl, halogen, preferably chlorine; nitrile, trifluoromethyl and carboxy; Y E is N or CR, preferably N; Preferably Z, is a disubstituted aryl, more preferably an o, substituted pyridinyl.
In another aspect of the present invention, there is disclosed a method for treating or preventing a disease or condition that is selected from the group consisting of fibrotic conditions, for example; ocular, cardiac, hepatic and pulmonary fibrosis, vi t eorret prolificatory inopathy, cicatricial pemphigoid, surgically induced fibrosis in the cornea, conjunctiva and Tenon's capsule and which comprises administering to a patient who needs it a compound represented by Formula I, II or III above.
Detailed description of the invention The new compounds having this general structure were synthesized and tested for the activity of the spi inagos-2-phosphate receptor by using the FLIPR assay. Cells expressing the receptor of interest (SIPi, S1P2 or S1P3) and a G protein (Gqi5 or G16) are loaded with fluo-4, a calcium-sensitive pigment. After extraction of the excess pigment by washing, the cells are placed in the FLIPR TETRA instrument. The reference fluorescence readings are taken before the addition of the compound to be evaluated. The agonists will fire the receiver to interact with the G protein, which leads to an increase in intracellular calcium. The increase in intracellular calcium causes an increase in the fluorescence of the cells, due to the presence of fluo-4. This increase in fluorescence is recorded by FLIPR TETRA. After the transient calcium signal drops to the reference point, the standard agonist ina-1-phosphate is added. If the test compound is an antagonist, an initial calcium signal will not be generated and the agonist will prevent the generation of a calcium signal from es inges ina-1-phosphate. The level of fluorescence is compared with that of the sphenes ina-1-phosphate and the EC50 or IC50 of the compound determined by the adjustment of the curve.
The compounds in the present invention are useful for the treatment of mammals, including humans, for diseases or conditions selected from the group consisting of ocular, cardiac, hepatic, and pulmonary fibrosis, chronic proliferative disease, cicatricial pemphigoid, fibrosis. surgically induced in the cornea, conjunctiva and Tenon's capsule.
Specific examples of the compounds of formula I include the compounds of Table 1 below.
TABLE 1 ?? Some compounds included within the scope of the invention can be prepared as illustrated in the procedures described below.
The invention is further illustrated by the following examples which are illustrative of a specific mode of practicing the invention and are not intended to be limiting of the scope of the claims.
Unless otherwise indicated, the following terms used throughout the present specification have the following meanings: DCM refers to dichloromethane.
THF refers to tetrahydrofuran.
EtOAc refers to ethylacetate. .
"Me" refers to methyl.
"Ph" refers to phenyl.
"Pharmaceutically acceptable salt" refers to those salts which retain the biological efficacy and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid , ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
"Alkyl" refers to a straight chain, branched or saturated cyclic hydrocarbon. Preferably, the alkyl group has from 1 to 12 carbons. More preferably, it is a lower alkyl of 1 to 7 carbons, more preferably 1 to 4 carbons. Typical alkenyl groups include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, = 0, = S, N02, halogen, dimethylamino and SH.
"Alkoxy" refers to an "O-alkyl" group.
"Aryl" refers to an aromatic group that has the less a ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, triahalomethyl, hydroxyl, SH, OH, N02, amine, thioether, cyano, alkoxy, alkyl and amino.
"Alkaryl" refers to an alkyl that is covalently linked to an aryl group. Preferably, the alkyl is lower alkyl.
"Carbocyclic" refers to saturated or unsaturated cyclic aliphatic hydrocarbon groups and aryl hydrocarbon where the ring atoms are exclusively carbon and comprise from 6 to 20 carbon atoms, including the ring atoms.
"Carbocyclic aryl" refers to an aryl group where the ring atoms are carbon.
"Heterocyclic" refers to cyclic groups wherein the ring atoms comprise carbon atoms and at least one oxygen, nitrogen and / or sulfur atom and may be saturated, unsaturated, ie having one or more double bonds, or aryl, and comprises up to 20 carbon atoms from 1 to 5 of the above heteroatoms.
"Heterocyclic aryl" refers to an aryl group having 1 to 3 heteroatoms as ring atoms, the rest of the ring atoms are carbon. The heteroatoms they include oxygen, sulfur and nitrogen.
"Hydrocarbyl" refers to a hydrocarbon radical having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and more preferably from 1 to 7 carbon atoms.
"Substituted hydrocarbyl" refers to a hydrocarbyl radical where one or more, but not all, hydrogen and / or carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical that includes a halogen atom , nitrogen, oxygen, sulfur or phosphorus, for example, fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, amide, ester, thioamide, thiol ester, amine, thioether, sulfonyl, etc.
"Amide" refers to -C (0) - -NH- -R 1, where R 1 is alkyl, aryl, alkylaryl or hydrogen.
"Ester" refers to -C (0) - -0- -R 1, where R 1 is alkyl, aryl or alkylaryl.
"Thioamide" refers to -C (S) - -NH- -R ', where R' is alkyl, aryl, alkylaryl or hydrogen.
"Tiol ester" refers to -C (O) -S-R 1, where R 'is alkyl, aryl, alkylaryl or hydrogen.
"Amines" refers to a group --N (R ") R '", where R "and R'" are independently selected from the group consisting of alkyl, aryl and alkylaryl.
"Thioether" refers to -S-R ", where R" is alkyl, aryl or alkylaryl.
"Sulfonyl" refers to -S (0) 2 -R "", where R "" is aryl, C (CN) = C-aryl, CH 2 CN, alkylaryl, sulfonamide, NH-alkyl, NH-alkylaryl or NH-aryl.
Likewise, alternatively, the substituent on the phenyl portion may be referred to as a substituent "o", "m" or "p" or a substituent 1, 3 or 4 respectively. (Obviously, substituent 5 is also a meta substituent and substituent 6 is an ortho) substituent.
The above compounds are evaluated to determine the activity of S1P2 in accordance with the above assay: The results are shown in Table 2 below.
The proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a 300 or 500 MHz Varian spectrometer in deuterated solvent. Chemical changes were recorded as d (delta) values in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm) and the multiplicities were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The data were reported in the following format: chemical change (multiplicity, coupling constants J in hertz (Hz), integrated intensity).
General Procedure A for the synthesis of substituted 4-isocyanatopyridine intermediates: Appropriate commercially available substituted isonicotinic acid (1.87 mmol) was dissolved in THF: DCM (4: 10ml) at 0 ° C. Oxalyl chloride (2.0M in DCM, 1.87ml, 3.75mmol) was added followed by 2 drops of DMF. The resulting solution was stirred at 0 ° C for 30 min and concentrated to dryness. The solid was dissolved in lOmL of acetone and cooled to 0 ° C. NaN3 (195 mg) was added, 3.00 mmol) in 1 mL of water. After being stirred at 0 ° C for 30 min, the reaction mixture was again concentrated to dryness and redissolved in benzene which was rapidly washed with ice water and dried over Na 2 SO 4 (The drying agent Na 2 SO 4 was filtered and the filtrate was filtered off. stirred at 110 ° C and cooled to 50 ° C to generate the title compound in situ This crude isocyanate was used in the next transformation without further purification.
Synthesis of intermediates 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridine and (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) methanamine: Intermediate title compounds were prepared from commercially available 3-fluoropyridine conformity with the following reaction scheme. 2- (3-Fluoro-pyridin-4-yl) -propan-2-ol: 3-fluoropyridine (11.0 g, 113.0 mmol) was treated in 100mL of THF with LDA (1.5M, 100.0 mL, 150.0 mmol) at -78 ° C for 50 min under argon. Acetone (28mL) was added and the resulting reaction mixture was stirred at -78 ° C to -40 ° C for 50 min. The reaction was quenched with aqueous NHC1 and extracted with ether. The combined organic layers were washed with H20 and brine, dried over Na2SO4 and concentrated in vacuo. Purification by MPLC (80g column, 0 to 40% of ethyl acetate in hexane as eluent) provided the title compound. Spectroscopic data: 1 H-NMR (300 MHz, CDCl 3): d ppm 1.65 (s, 6 H), 7.27 (dd, J = 5.57 Hz, 1 H), 8, 36-8, 39 ( m, 2 H). 3 - . 3-Fluoro-4-isopropyl-pyridine: 2- (3-fluoro-pyridin-4-yl) -propan-2-ol (from the previous step, 6.40 g, 41.3 mmol) was dissolved in 50 mL of aqueous solution of HI 57%. Red phosphorus (4.48 g, 144.0 mmol) was added and the mixture was stirred at 140 ° C for 5 hours. The reaction mixture was cooled to room temperature, neutralized with aq NaOH. 5 N and extracted with ether. The combined organic layers were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. The title compound was obtained by distillation. Spectroscopic data: 1 H-NMR (300 MHz, CDC13): d ppm 1.27 (d, J = 7.04 Hz, 6 H), 3.25 (hept, J = 7.04 Hz, 1 H), 7 , 21 (dd, J = 5.44 Hz, 1 H), 8.33-8.36 (m, 2 H). 1- (3-Fluoro-4-isopropyl-pyridin-2'-yl) -ethanol: 1,4-diazabicyclo [2, 2, 2] octane (6.16 g, 55.0 mmol) was dissolved in ether ( lOOmL) at -40 ° C. P-BuLi (2.5M in hexane, 57.50 mL, 23.0 mmol) was added and the resulting reaction mixture was stirred at -20 ° C for 1 hour. The reaction solution was cooled to -60 ° C and 3-fluoro-4-isopropyl-pyridine (which was obtained from the previous step, 7.00 g, 50.0 mmol) was introduced. Stirring was continued for 1 hour and acetaldehyde (3 mL) was added. The solution was left Heat at -30 ° C for 1 hour and quench with aqueous NH 4 Cl. The aqueous layer was extracted with ether. The combined extract was dried over Na2SO4 and concentrated. Purification by MPLC (80g column, 0 to 15% ethyl acetate in hexane as eluent) afforded the title compound. Spectroscopic data: ^ - MR (300 MHz, CDC13): d ppm 1.27 (d, J = 7.04 Hz, 3 H), 1.29 (d, J "= 7.04 Hz, 3 H), 1.50 (d, J = 6.44 Hz, 3 H), 3.28 (hept, J = 7.04 Hz, 1 H), 5.13 (q, J = 6.44 Hz, 3 H) , 7.18 (dd, J = 5.41 Hz, 1 H), 8.29 (d, J = 5.27 Hz, 1 H). 1- (3-Fluoro-4-isopropyl-pyridin-2-yl) -ethanone: 1- (3-fluoro-4-isopropyl-pyridin-2-yl) -ethanol (which was prepared in the previous step, was dissolved, 3.00 g, 16.39 mmol) in 60 mL of anhydrous toluene. Mn02 (4.05 g, 46.55 mmol) was added and the resulting mixture was stirred at 140 ° C overnight. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and purified by MPLC (80g, 0 to 20% ethyl acetate in hexane) to give the title compound. Spectroscopic data: ^ -NMR (300 MHz, CDC13): d ppm 1.28 (d, J = 6.73 Hz, 6 H), 2.70 (s, 3 H), 3.35 (hept, J = 6.73 Hz, 1 H), 7.38 (dd, J = 5.13 Hz, 1 H), 8.39 (d, J = 4.69 Hz, 1 H). 7-Isopropyl-l, 3-dimethyl-l-pyrazolo [4,3-b] pyridine: 1- (3-fluoro-4-isopropyl-pyridin-2-yl) -ethanone (which was prepared in step previous, 2.50 g, 15.15 mmol) and methyl hydrazine (1.04 g, 23.00 mmol) in 8 mL of glycol. The reaction solution was stirred at 140 ° C for 2 hours. After cooling, it was quenched with water, extracted with DCM, washed with water, brine and concentrated. Column chromatography using 15 to 35% ethyl acetate in hexane as eluent afforded the title compound as a light yellow solid. Spectroscopic data: "" | H-NMR (300 MHz, CDC13): d ppm 1.39 (d, J = 6.73 Hz, 6 H), 2.64 (s, 3 H), 3.65 (hept , J = 6.73 Hz, 1 H), 4.23 (s, 3 H), 7.14 (d, J = 4.69 Hz, 1 H), 8.44 (d, J = 4.69 Hz 1 H). 7-1-propyl-1,3-dimethyl-1H-pyrazolo [4,3-b] pyridine: 7-isopropyl-1,3-dimeti-1H-pyrazolo [4,3-jb] pyridine prepared in the previous step, 2.50 g, 13.22 mmol) in 100 mL of chloroform was added 77% MCPBA (5.91 g, 26.44 mmol) at 0 ° C. The resulting solution was stirred at 90 ° C for 3 hours. After cooling, it was neutralized with NaHCO3 aq. and extracted with DCM. The combined organic phases were washed with water, brine and concentrated. Column chromatography using 5% 7N NH3 in MeOH / DCM as eluent afforded the title compound as a white solid. Spectroscopic data: 1 H-NMR (300 MHz, CDCl 3): d ppm 1.37 (d, J "= 6.73 Hz, 6 H), 2.83 (s, 3 H), 3.60 (hept, J "= 6.73 Hz, 1 H), 4.21 (s, 3 H), 6.78 (d, J = 6.30 Hz, 1 H), 8.01 (d, j = 6, 30 Hz 1 HOUR) . 5 - . 5-Chloro-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridine: to a solution of 4-oxide of 7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridine (which was obtained from the previous step, 2.26 g, 11.00 mmol) in 30 mL of toluene was added P0C13 (3.37 g, 22.00 mmol). The resulting reaction mixture was stirred at 90 ° C for 2 hours and concentrated. DCM added The organic layer was washed with water and brine, then dried over Na 2 SO and concentrated. Column chromatography with DCM separated two isomers and gave the title compound as a white solid. Spectroscopic data: XH-NMR (300 MHz, CDC13): d ppm 1.39 (d, J = 6.73 Hz, 6 H), 2.58 (s, 3 H), 3.62 (hept, J = 6.73 Hz, 1 H), 4.21 (s, 3 H), 7, 11 (s, 1 H). (7-Isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) -hydrazine: 5-chloro-7-isopropyl-1,3-dimethyl-1H-pyrazolo [ 4, 3 - £ > ] pyridine (which was obtained from the previous step, 620 mg, 2.68 mmol) and 6 mL of hydrazine monohydrate in 4 mL of EtOH. The reaction solution was stirred at 120 ° C for 3 days. The reaction solution was concentrated under reduced pressure. MeOH was added to the residue and concentrated again. This was repeated several times until a solid formed. The solid was collected by filtration as the title compound. Spectroscopic data: 1H-MR (300 MHz, CDC13): d ppm 1.34 (d, J = 6.73 Hz, 6 H), 2.52 (s, 3 H), 3.56 (hept, .7 = 6.73 Hz, 1 H), 4.15 (s, 3 H), 6.59 (S, 1 H). 7-Isopropyl-l, 3-dimethyl-lH-pyrazolo [4,3-b] pyridine-5-carbonitrile: N-oxide of a solution of 7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-Jb] pyridine (which was obtained from the previous step, 1.06 g, 5.17 mmol) and TEA (1.08 mL, 7.73 mmol) in 20 mL CH3C was added TMS cyanide (1, 37 g, 10.34 mmol). The resulting solution was stirred at reflux for 18 hours. Another 0.5 mL of TMS cyanide was added and the reaction continued for another 7 hours. The solvent was removed under reduced pressure and the residue was loaded on a column of silica gel and eluted with 20 to 30% ethyl acetate to provide the desired title compound as a solid. Spectroscopic data: 1 H-NMR (300 MHz, CDC13): d ppm 1.40 (d, J "= 6.74 Hz, 6 H), 2.64 (s, 3 H), 3.69 (hept, J = 6.74 Hz, 1 H), 4.26 (s, 3 H), 7.46 (s, 1 H).
C- (7-Isopropyl-l, 3-dimethyl-lH-pyrazolo [4,3-b] pyridin-5-yl) -methylamine: 7-Isopropyl-1,3-dimethyl-1-pyrazolo [4,3-jb] pyridine-5-carbonitrile (from the previous step, 91.05 g, 5.15 mmol) was dissolved in EtOH: THF: HC1 conc . (25 mL: 10 mL: 1, 5 mL). 400 mg of 10% Pd / C was added and the reaction mixture was stirred under a hydrogen balloon overnight. The catalyst was filtered and the filtrate was concentrated under reduced pressure to provide the title compound as a white solid. Spectroscopic data: ^ -NMR (300 MHz, CD30D): d ppm 1.41 (d, J "= 6.74 Hz, 6 H), 2.56 (s, 3 H), 3.77 (hept, J "= 6.74 Hz, 1 H), 4.02 (s, 2 H), 4.21 (s, 3 H), 7.36 (s, 1 H).
General Procedure B for the synthesis of substituted ureas: A suitably substituted amine or hydrazine, prepared above, and a suitably substituted isocyanate (both commercially available or that prepared above, 1.1 eq) were dissolved in 8 mL of THF. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed under reduced pressure. The title compound was isolated by column chromatography using 30 to 75% ethyl acetate in hexane, further purification was performed by recrystallization from MeOH.
Example 1 Synthesis of N- (3,5-dichlorophenyl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from (7-isopropyl-1,3-dimethyl-1-pyrazolo [4,3-J] pyridin-5-yl) -hydrazine, prepared above, and 3,5-dichlorophenyl isocyanate commercially available in accordance with General Procedure B, which was described above.
N- (3,5-Dichlorophenyl) -2- (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the title compound was obtained from isocyanate of 3,5-dichlorophenyl (commercially available, 113 mg, 0.60 mmol), 5-hydrazini-1-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-jb] pyridine (prepared above, 110 mg, 0.50 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD30D) d ppm 1.38 (d, J = 6.73 Hz, 6 H), 2.44 (s, 3 H), 3.70 (hept, J = 6, 73 Hz, 1 H), 4.14 (s, 3 H), 6.85 (s, 1 H), 7.02 (dd, J = 1, 76 Hz, 1 H), 7.55 (d, J = 1, 76 Hz, 2 H).
Example 2 Synthesis of 1- (2,6-dichloropyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-b] pyridin-5-yl) methyl) rea: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3] pyridin-5-yl) methanamine, prepared above, and 2,6-dichloro-4-isocyanatopyridine commercially available in accordance with General Procedure B, which was described above. 1- (2,6-Dichloropyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: the compound of the title was obtained from 2,6-dichloro-4-isocyanatopyridine (commercially available, 180 mg, 0.95 mmol), (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridine- 5-yl) methanamine (prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD30D) d ppm 1.40 (d, J = 6.73 Hz, 6 H), 2.57 (s, 3 H), 3.74 (hept, J = 6, 73 Hz, 1 H), 4.22 (s, 3 H), 4.61 (s, 2 H), 7, 33 (s, 1 H), 7.48 (s, 2 H).
Example 3 Synthesis of iV- (2-Butyl-6-chloropyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] iridin-5-yl) hydrazinecarboxamide: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-jb] pyridin-5-yl) -hydrazine, prepared above, and 2-Butyl-6-chloro -4-isocyanato-pyridine in accordance with General Procedure B, which was described above. The intermediate 2-Butyl-6-chloro-4-isocyanato-pyridine was prepared from in accordance with General Procedure A and was used in situ without further purification. 2-Butyl-6-chloro-isonicotinic acid .- The title compound was prepared from ethyl 2,4-dioxo-octanate according to the method named in the literature in reference 1. The spectroscopic data coincide with those reported in the references and also in the present: 1 H-NMR (300 MHz, CD30D): d ppm 0.96 (t, J = 7.33 Hz, 3 H), 1.33-1.43 (m, 2 H), 1.66-1.76 (m, 2 H), 2.82 (t, J = 7.62 Hz, 2 H), 7.70 (s, 1 H). 2-Butyl-6-chloro-4-isocyanato-pyridine: the title compound was prepared from butyl-6-chloro-isonicotinic acid (which was prepared above, 400 mg, 1.87 mmol), oxalyl chloride ( 2.0 M in DCM, 1.87 mL, 3.75 mmol) in accordance with General Procedure A, which was described above. The crude title compound was used in the next step without further purification.
N- (2-Butyl-6-chloropyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the compound of title was obtained from 2-butyl-6-chloro-4-isocyanato-pyridine (prepared above), 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pi azolo [4, 3 -] pi idine ( prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1H NMR (300 MHz, CD3OD) d ppm 0.91 (t, J = 7.32 Hz, 3 H), 126 (m, 2 H), 1.35 (d, J = 6.73 Hz, 6 H), 1.61 (m, 2 H), 2.43 (s, 3 H), 2.61 (t, J = 7.68 Hz, 2 H), 3.65 (hept, J = 6.73 Hz, 1 H), 4.12 (s, 3 H), 6.82 (s, 1 H), 7.30 (S, 1 H), 7.55 (s, 1 H).
Example 4 Synthesis of N- (2-chloro-6-ethoxypyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-Jb] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-jb] pyridin-5-yl) -hydrazine, prepared above, and 2-chloro-6-ethoxy -4-isocyanatopyridine in accordance with General Procedure B, which was described above. Intermediate 2-chloro-6-ethoxy-4-isocyanatopyridine was prepared according to General Procedure A and used in situ without further purification. 2-Chloro-6-ethoxy-i-sonicotinic acid: the title compound was prepared from 2,6-dichloropyridine-4-carboxylic acid according to the method reported in reference 2. The spectroscopic data coincide with the that are reported in the reference and also in the present. 1 H-NMR (300 MHz, CD 3 OD): d ppm 1.38 (t, J "= 7.04 Hz, 3 H), 4.36 (q, J = 7.04 Hz, 2 H), 7.17 (d, J "= 1, 18 Hz, 1 H), 7.39 (d, J = 1, 18 Hz, 1 H). 2-Chloro-6-ethoxy-4-isocyanato-pyridine: the title compound was prepared from 2-c-loro-6-ethoxy-i sonicotico acid (which was prepared above), oxalyl chloride (2, 0 M in DCM) in accordance with General Procedure A, which was described above. The crude title compound was used in the next step without further purification.
N- (2-Chloro-6-ethoxypyridin-4-yl) -2- (7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the compound of title was obtained from 2-c parrot-6-et oxy-4-i soc ianat o-pi ridine (prepared above), 5-hydrazin 1 -7-i sopropi 1-l, 3-dimethyl-lif-pyrazolo [4,3-jb] pyridine (prepared above, 180 mg, 0.82 mmol) in accordance with protocols indicated in General Procedure B above. Spectroscopic data: NMR (300 MHz, CD3OD) d ppm 1.33 (t, J = 7.04 Hz, 3 H), 1.37 (d, J = 6.73 Hz, 6 H), 2.44 (s, 3 H), 3.67 (hept, J = 6.73 Hz, 1 H), 4.14 (s, 3 H), 4.24 (q, J = 7.04 Hz, 2 H), 6.83 (s, 1 H), 6.92 (s, 1 H), 7.10 (s, 1 H).
Example 5 Synthesis of 1- (3,5-dichlorophenyl) -3- ((1,3,7-trimethyl-1 H -pyrazolo [4, 3 ± >] pyridin-5-yl) methyl) urea: The title compound was generated from (1,3,7-trimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) methanamine which was prepared using the procedure described above for (7-isopropyl) 3,5-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methanamine and 3,5-dichlorophenyl isocyanate, commercially available, according to General Procedure B, which was described above. 1- (3, 5-Dichlorophenyl) -3- ((1,3, 7-trimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: the title compound was obtained from isocyanate of 3, 5-dichlorophenyl (commercially available, 170 mg, 0.90 mmol), (1,3,7-trimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methanamine (prepared above, 160 mg, 0.84 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD30D) d ppm 2.47 (s, 3 H), 2.74 (s, 3 H), 4.14 (s, 3 H), 4.47 (d, J) = 4.69 Hz, 2 H), 7.01 (dd, .7 = 2.07 Hz, 1 H), 7.10 (bs, 1 H), 7.21 (s, 1 H), 7, 42 (d, J = 2.07 Hz, 2 H), 9.45 (s, 1 H).
Example 6 Synthesis of iV- (2,6-dichloropyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-1 H -pyrazolo [4,3- [beta]] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-ib] pyridin-5-yl) -hydrazine, prepared above, and 2,6-dichloro-4 -isocyanopyridine commercially available in accordance with General Procedure B, which was described above.
N- (2,6-Dichloropyridin-4-yl) -2- (7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the title compound is obtained from 3,5-dichlorophenyl isocyanate (commercially available, 124 mg, 0.66 mmol), 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-jblpyridine (prepared above, 120 mg, 0.55 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD30D) d ppm 1.37 (d, J = 6.73 Hz, 6 H), 2.44 (s, 3 H), 3.68 (hept, J = 6, 73 Hz, 1 H), 4.14 (s, 3 H), 6.82 (s, 1 H), 7.63 (s, 2 H).
Example 7 Synthesis of N- (3,5-bis (trifluoromethyl) phenyl) -2- (7-isopropyl-1,3-dimethyl-β-pyrazolo [4, 3-Jb] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from 5-hydrazinyl-7-isopropyl -1,3-dimethyl-1H-pyrazolo [4,3-b] pyridine, prepared above, and 4-isocyanato-2,6-bis (trifluoromethyl) ) pyridine, commercially available, in accordance with General Procedure B, which was described above.
N- (3,5-Bis (trifluoromethyl) phenyl) -2- (7-isopropyl-1,3-dimethyl-IH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the title compound is obtained from 4-isocyanato-2,6-bis (trifluoromethyl) pyridine (commercially available, 117 mg, 0.44 mmol), 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3 - ib] pyridine (prepared above, 80 mg, 0.36 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1H NMR (300 MHz, CD30D) d ppm 1.38 (d, J = 6.73 Hz, 6 H), 2.44 (s, 3 H), 3.68 (hept, J = 6.73 Hz, 1 H) , 4.14 (s, 3 H), 6.86 (s, 1 H), 7, 53 (s, 1 H), 8, 19 (s, 2 H).
Example 8 Synthesis of N- (3-chloro-5-methoxypyridin-4-yl) -2- (7- isopropyl-1,3-dimethyl-lJ-pyrazolo [4,3-b] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from (7- isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-h] pyridin-5-yl) -hydrazine, prepared above, and 2-chloro-6-methoxy -4- isocyanatopyridine in accordance with General Procedure B, which was described above. The intermediate 2-chloro-6-methoxy-4-isocyanatopyridine was prepared according to General Procedure A and used in situ without further purification.
N- (3-Chloro-5-methoxypyridin-4-yl) -2- (7-isopropyl-1, 3-dimethyl-1 H -pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the compound of title was obtained from 2-chloro-6-methoxy-4-isocyanato-pyridine (which was prepared above in accordance with General Procedure A, crude), 5-hydrazini-1-7-isopropyl-1,3-dimethyl-1H- pyrazolo [4, 3-b] pyridine (prepared above, 140 mg, 0.64 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1H NMR (300 MHz, CD30D) d ppm 1.37 (d,? 7 = 6.80 ??, 6 H), 2.44 (s, 3 H), 3.69 (hept, J = 6.80 Hz, 1 H), 3.38 ( s, 3 H), 4.14 (s, 3 H), 6.83 (s, 1 H), 6, 95 (s, 1 H), 7, 01 (s, 1 H).
Example 9 Synthesis of 1- (2,6-dichlorophenyl) -3- ((7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4,3-2?] Pyridin-5-yl) methyl) ure: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-yl] pyridin-5-yl) methanamine, prepared above, and commercially available 1, 3 - dichloro-5-isocyanatobenzene in accordance with General Procedure B, which was described above. 1- (3,5-Dichlorophenyl) -3- ((7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: the title compound was obtained of 1,3-dichloro-5-isocyanatobenzene (commercially available, 188 mg, 1.0 mmol), (7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-jb] pyridin-5-yl) methanamine (prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data:? NMR (300 MHz, CD30D) d ppm 1.40 (d, -7 = 6.73 Hz, 6 H), 2.57 (s, 3 H), 3.76 (hept, , 7 = 6, 73Hz, 1 H), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.99 (dd, J- = l, 76Hz, 1 H), 7, 34 (s, 1 H), 7.43 (d, J = 1, 76 Hz, 2 H).
Example 10 Synthesis of 1- (2-chloro-6-methoxypyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: The title compound was generated from (7-isopropyl-1,3-dimethyl-l, -pyrazolo [4, 3-b] pyridin-5-yl) methanamine, prepared above, and 2-chloro-4-isocyanato- 6-methoxypyridine (which was prepared in accordance with General Procedure A, which was described above) in accordance with General Procedure B, which was described above. 1- (2-chloro-6-methoxypyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea; the title compound was obtained from 2-chloro-4-isocyanato-6-methoxypyridine (prepared above, crude, 1.0 mmol), (7-isopropyl-1,3-dimethyl-1H-pyrazole [4, 3 - £ >] pyridin-5-yl) methanamine (prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: ""? NMR (300 MHz, CD3OD) d ppm 1.40 (d, J = 6.73 Hz, 6 H), 2.57 (s, 3 H), 3.76 (hept, J = 6.73 Hz, 1 H ), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.82 (d, .7 = 1.76 Hz, 1 H), 7.06 (d, J = l, 76 Hz, 1 H), 7.33 (s, 1 H).
Example 11 Synthesis of N- (2-chloro-6-propylpyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4,3-b] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4,3-Jb] pyridin-5-yl) -hydrazine, prepared above, and 2-chloro-4-isocyanate -6-propylpyridine in accordance with General Procedure B, which was described above. The intermediate 2-chloro-4-isocyanato-6-propylpyridine was prepared according to General Procedure A and used in situ without further purification.
N- (2-Chloro-6-propylpyridin-4-yl) -2- (7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the compound of title was obtained from 2-chloro-4-isocyanato-6-propylpyridine (prepared above), 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-j] pyridine (prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: H NMR (300 Hz, CD30D) d ppm 0.94 (t, J = 7.32 Hz, 3 H), 1.37 (d, J = 6.73 Hz, 6 H), 1.69 (m, 2 H), 2.44 (s, 3 H), 2.61 (t, J = 7.68 Hz, 2 H), 3.68 (hept, J = 6.73 Hz, 1 H) , 4.14 (s, 3 H), 6.84 (s, 1 H), 7.37 (s, 1 H), 7. 57 (s, 1 H).
Example 12 Synthesis of 1- (2-chloro-6-propylpyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-Jb] pyridin-5-yl) methanamine, prepared above, and 2-chloro-4-isocyanate 6-propylpyridine in accordance with General Procedure B, which was described above. The intermediate 2-chloro-4-isocyanato-6-propylpyridine was prepared according to General Procedure A and used in situ without further purification. 1- (2-Chloro-6-propylpyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: he The title compound was obtained from 2-chloro-4-isocyanato-6-propylpyridine (prepared above), (7-isopropyl-l, -3-dimethyl-lH-pyrazolo [4, 3-i] pyridin-5-yl) methanamine (prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1H NMR (300 MHz, CD3OD) d ppm 0.94 (t,, 7 = 7.32 Hz, 3 H), 1.37 (d, J = 6.73 Hz, 6 H), 1, 69 (m, 2 H), 2.44 (s, 3 H), 2.61 (t, J = 7.68 Hz, 2 H), 3.68 (hept, J = 6.73 Hz, 1 H ), 4.14 (s, 3 H), 6.84 (s, 1 H), 7.37 (S, 1 H), 7.57 (S, 1 H).
Example 13 Synthesis of 1- (2-chloro-6-ethoxypyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-lff-pyrazolo [4,3-Jb] pyridin-5-yl) methyl) urea: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-e £>] pyridin-5-yl) methanamine, prepared above, and 2-chloro-6- ethoxy-4-isocyanatopyridine in accordance with General Procedure B, which was described above. The intermediate 2-chloro-6-ethoxy-4-isocyanatopyridine was prepared in accordance with General Procedure A and was used in in situ without further purification. 1- (2-Chloro-6-ethoxypyridin-4-yl) -3- ((7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) ethyl) urea: the title compound was obtained from 2-chloro-6-ethoxy-4-isocyanatopyridine (prepared above), (7-isopropyl-1,3-dimethyl-IH-pyrazolo [4, 3-jb] pyridin-5-yl) methanamine (prepared above, 200 mg, 0.92 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD3OD) d ppm 1.34 (t, J = 7.04 Hz, 3 H), 1.39 (d, J = 6.73 Hz, 6 H), 2.57 ( s, 3 H), 3.76 (hept, J = 6.73 Hz, 1 H), 4.21 (s, 3 H), 4.25 (q, J = 7.04 Hz, 2 H), 4.59 (s, 2 H), 6.78 (d, J = 1, 46 Hz, 1 H), 7.04 (d, J = 1, 46 Hz, 1 H), 7.33 (s, 1 HOUR) .
Example 14 Synthesis of 1- (2-chloro-6-propoxypyridin-4-yl) -3- ((7- isopropyl-1,3-dimethyl-IH-pyrazolo [4, 3-Jb] pyridin-5-yl) methyl) urea: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3 ± >] pyridin-5 i 1) methanamine, prepared above, and 2-chloro-4 - isocyanate-6-propoxypyr idine in accordance with General Procedure B, which was described above. The intermediate io 2-c-loro-4-isocyanate -6-propoxypyridine was prepared according to General Procedure A and used in situ without further purification. 1 - . 1 - (2-Chloro-6-propoxypyridin-4-yl) -3 - ((7-i-sopropi-1,3-dimet-1-IH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: the title compound was obtained from 2-chloro-4-isocyanato-6-propoxypyridine (prepared above), (7-isopropi 1-l, 3-dimet il-1H-pi just [4, 3 - £ >] pyridin-5-yl) methanamine (prepared above, 180 mg, 0.82 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD30D) d ppm 1.00 (t, J = 7.32 Hz, 3 H), 1.40 (d, J = 6.73 Hz, 6 H), 1.75 ( m, 2 H), 2.57 (s, 3 H), 3.76 (hept, .7 = 6.73 Hz, 1 H), 4.15 (t, J = 6.60 Hz, 2 H) , 4.21 (s, 3 H), 4.59 (s, 2 H), 6.78 (d, J = 1, 46 Hz, 1 H), 7.04 (d, J = 1, 46 Hz , 1 H), 7.34 (s, 1 H).
Example 15 Synthesis of N- (2-chloro-6-propoxypyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lff-pyrazolo [4, 3 -ib] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-bipyridine, prepared above, and 2-chloro-4-isocyanato-6-propoxypyridine in accordance with General Procedure B, which was described above. The intermediate 2-chloro-4-isocyanato-6-propoxypyridine was prepared according to General Procedure A and used in situ without further purification.
N- (3-Chloro-5-propoxyphenyl) -2- (7-isopropyl-l, 3-dimethyl-γ-phenyl) [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the title compound is obtained from 2-chloro-isocyanato-6-propoxypyridine (which was prepared above according to General Procedure A, crude), 5-hydrazine 1-7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-jb] pyridine (prepared above, 160 mg, 0.73 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 1 H NMR (300 MHz, CD30D) 5 ppm 1.00 (t, .7 = 7.34 Hz, 3 H), 1.38 (d, J- = 6.73 Hz, 6 H), 1 , 74 (m, 2 H), 2.44 (s, 3 H), 3.67 (hept, J = 6.73 Hz, 1 H), 4.12-4.17 (m, 5 H), 6.83 (s, 1 H), 6.94 (s, 1 H), 7.19 (s, 1 H).
Example 16 Synthesis of N- (2-butoxy-6-chloropyridin-4-yl) -2- (7- isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-Jb] pyridin-5-yl) hydrazinecarboxamide: The title compound was generated from 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-j] pyridine, prepared above, and 2-butoxy-6-chloro-4-isocyanatopyridine in accordance with General Procedure B, which was described above. The 2-butoxy-6-chloro-4-isocyanatopyridine intermediate was prepared according to General Procedure A and used in situ without further purification.
N- (2-Butoxy-6-chloropyridin-4-yl) -2- (7-isopropyl-l, 3-dimethyl-1H-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the compound of title was obtained from 2-butoxy-6-chloro-4-isocyanatopyridine (which was prepared above in accordance with General Procedure A, crude), 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [ 4, 3-b] pyridine (prepared above, 160 mg, 0.73 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: XH N R (300 MHz, CD3OD) d ppm 0.97 (t, J = 7.34 Hz, 3 H), 1.38 (d, J = 6.73 Hz, 6 H), 1.46 (m, 2 H), 1.71 (m , 2 H), 2.44 (s, 3 H), 3.68 (hept, J = 6.73 Hz, 1 H), 4.14 (s, 3 H), 4.20 (t, J = 6.44 Hz, 2 H), 6.83 (s, 1 H), 6, 93 (s, 1 H), 7, 19 (s, 1 H).
Example 17 Synthesis of 1- (2-butoxy-6-chloropyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-1-pyrazolo [4,3-b] pyridin-5-yl) methyl) urea: The title compound was generated from (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-jb] pyridin-5-yl) methanamine, prepared above, and 2-butoxy-6-chloro- 4-isocyanatopyridine in accordance with General Procedure B, which was described above. The 2-butoxy-6-chloro-4-isocyanatopyridine intermediate was prepared according to General Procedure A and used in situ without further purification. 1- (2 -Butoxy-6-chloropyridin-4-yl) -3- ((7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea: the title compound was obtained from 2-chloro-4-isocyanato-6-propoxypyridine (prepared above), (7-isopropyl-1,3-dimethyl-l, -pyrazolo [4, 3-jb] pyridin-5- il) methanamine (prepared above, 170 mg, 0.78 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: H NMR (300 MHz, CD3OD) d ppm 0.97 (t, J = 7.32 Hz, 3 H), 1.40 (d, .7 = 6.73 Hz, 6 H), 1 , 50 (m, 2 H), 1.72 (m, 2 H), 2.57 (s, 3 H), 3.76 (hept, J = 6.73 Hz, 1 H), 4.20 (t, J = 6.44 Hz, 2 H), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.80 (d, J = 1, 46 Hz, 1 H), 7.04 (d, J = 1, 46 Hz, 1 H), 7, 34 (s, 1 H).
Example 18 Synthesis of N- (2-ethoxypyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-β-pyrazolo [4, 3-b] pyridin-Sil) hydrazinecarboxamide: The title compound was generated from 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3- £ > ] pyridine, prepared above, and 2-ethoxy-4-isocyanatopyridine in accordance with General Procedure B, which was described above. The 2-ethoxy-4-isocyanatopyridine intermediate was prepared according to General Procedure A and used in situ without further purification.
N- (2-Ethoxypyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the title compound was obtained from 2-ethoxy-4-isocyanatopyridine (which was prepared above according to General Procedure A, crude), 5-hydrazinyl-7- isopropyl-1,3-dimethyl-1H-pyrazolo [, 3-b] pyridine (prepared above, 160 mg, 0.73 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: XH NMR (300 MHz, CD3OD) d ppm 1.34 (t, .7 = 7.04 Hz, 3 H), 1.38 (d, .7 = 6.73 Hz, 6 H), 2 , 44 (s, 3 H), 3.69 (hept, J = 6.73 Hz, 1 H), 4.14 (s, 3 H), 4.24 (q, J = 7.04 Hz, 2 H), 6.84 (s, 1 H), 7.04-7.07 (m, 2 H), 7.86 (d, J = 6.00 Hz,, 1 H).
Example 19 Synthesis of N- (5-chloro-2,4-dimethoxyphenyl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4,3-b] iridin-5-yl) hydrazinecarboxamide: The title compound was generated from 5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo [4,3-b] pyridine, prepared above, and commercially available l-chloro-5-isocyanato-2 , 4-dimethoxybenzene in accordance with General Procedure B, which was described above.
N- (5-Chloro-2,4-dimethyl phenyl) -2 - (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide: the title compound was obtained from 1-chloro-5-isocyanato-2, -dimethoxybenzene and 5-hydrazine-1-7-sopropyl-1,3-dimet i 1-lH-pi azolo [4,3-jb] pyridine (prepared above, 160 mg, 0.73 mmol) in accordance with the protocols indicated in General Procedure B above. Spectroscopic data: 2 H NMR (300 MHz, CD30D) d ppm 1.37 (d, J = 6.73 Hz, 6 H), 2.45 (s, 3 H), 3.68 (hept, J "= 6 , 73 Hz, 1 H), 3.82 (s, 3 H), 3.85 (s, 3 H), 4.14 (s, 3 H), 6.70 (s, 1 H), 6, 86 (s, 1 H), 8.01 (s, 1 H).
Example 20 Synthesis of N- (3,5-dichlorophenyl) -2- (4-methyl-l, 8-naphthi-idin-2-yl) hydrazinecarboxamide The title compound was generated from N- (pyridin-2-yl) pivalamide in accordance with the chemistry described in the following reaction scheme. The intermediaries were separated and characterized. reaction scheme N- (3-Acetylpyridin-2-yl) pivalamide: to a solution of N- (pyridin-2-yl) pivalamide (2.0 g, 11.22 mmol) in THF at -78 ° C was added 9.4 mL (2.1 eq) of n-BuLi. The resulting mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled to -78 ° C after which N-methoxy-N-methylacetamide (1.2 g, 1.1 eq) was added as a solution in THF. The resulting mixture was stirred at room temperature for 2 hours. This is inactive on ice-H20. The resulting mixture was extracted with CH2C12 (3X 20 mL) and the combined organic extracts were washed with H20 (2x 20 mL), brine (lx 20 mL), then dried over gS04. Concentration and purification by MPLC afforded N- (3-acetylpyridin-2-yl) pivalamide (1.62 g, 65%). Spectroscopic data: XH NMR (300 MHz, cdcl3) d ppm 1.36 (s, 9 H) 2.65 (s, 3 H) 7.09 (dd, J = 7.76, 4.83 Hz, 1 H ) 8.17 (dd, J = 7.76, 1.90 Hz, 1 H) 8.64 (dd, J = 4.69, 2.05 Hz, 1 H) 11.49 (br. S., 1 HOUR) .
Tere-Butyl 3-hydroxy-3- (2-pivalamidopyridin-3-yl) butanoate: To a solution of 9.5 mL (2.1 eq) of LDA in 15 mL THF at -78 ° C was added 2, 0 mL of t-butyl acetate (2.1 eq.). The resulting mixture was stirred at -78 ° C for 30 minutes after which a solution of N- (3-acetylpyridin-2-yl) pivalamide (1.52 g, 6.90 mmol) in THF was added dropwise. The resulting reaction mixture was stirred at -78 ° C for 30 minutes and brought to room temperature. The reaction mixture was quenched with saturated NH 4 Cl. The resulting mixture was extracted with EtOAc (3X 20 mL) and the combined organic extracts were washed with H20 (2x 20 mL), brine (Ix 20 mL), dried over MgSO4 and concentrated to provide the title compound (1, 40 g, 61%). Spectroscopic data: HNR (300 MHz, cdcl3) d ppm 1.33 (s, 9 H) 1.44 (s, 9 H) 1.58 (s, 3 H) 2.65 (d, J = 16.70 Hz, 1 H) 3.06 (d, .7 = 16.70 Hz, 1 H) 5.54 (s, 1 H) 6.96 (dd, J = 7.76, 4.83 Hz, 1 H ) 7.43 (dd, J = 7.91, 1.76 Hz, 1 H) 8.45 (dd, J = 4.98, 1.76 Hz, 1 H) 10, 29 (s, 1 H) . 4-Methyl-l, 8-naphthyridin-2 (1H) -one: a solution of 1.3 g of tere-butyl 3-hydroxy-3- (2-pivalamidopyridin-3-yl) butanoate (3.9 mmol ) in 2 mL of 3N HCl was microwaved at 160 ° C for 5 minutes. The resulting mixture was washed with Et20 (2 x 10 mL). The aqueous layer was basified using saturated K2C03. The precipitate that formed was filtered and washed with water to provide 440 mg (71%) of the desired compound of Title. Spectroscopic data: ?? NMR (300 MHz, DMSO-d6) d ppm 2.40 (d, .7 = 1.17 Hz, 3 H) 6.43 (s, 1 H) 7.24 (dd, J = 7.91, 4 , 69 Hz, 1 H) 8.12 (dd, J = 7.91, 1.76 Hz, 1 H) 8.49 (dd, J = 4.69, 1.76 Hz, 1 H) 11.92 (br. s. (1 H). 2-Chloro-4-methyl-l, 8-naphthyridine: to a solution of 4-methyl-1, 8-naphthyridin-2 (1H) -one (440 mg, 2.75 mmol) in toluene was added 302 uL of POC13 (1.2 eq). The resulting mixture was refluxed at 120 ° C for 3 hours. After cooling to room temperature the reaction mixture was quenched in ice-H20 and extracted with EtOAc (3X 10 mL). The combined organic extracts were washed with H20 (2x 15 mL), brine (lx 20 mL), and dried over MgSO4. Concentration and purification by MPLC provided the desired 2-chloro-4-methyl-l, 8-naphthyridine (330 mg, 67%). Spectroscopic data: XH NMR (300 MHz, cdcl3) d ppm 2.72 (s, 3 H) 7.35 (d, J = 1, 17 Hz, 1 H) 7.53 (dd, J = 8.20, 4.40 Hz, 1 H) 8.36 (dd, J = 8.35, 1.90 Hz, 1 H) 9.10 (dd, 1 H). 2-Hydrazinyl-4-methyl-l, 8-naphthyridine: a solution of 2-chloro-4-methyl-l, 8-naphthyridine (330 mg, 1.8 mmol) in NH 2 NH 2 was refluxed at 130 ° C for 2 hours. The reaction mixture was cooled to room temperature, the remaining NH2NH2 was removed in a rotary evaporator. The residue was taken up in 20 mL of CH2C12, the mixture was washed with saturated NaHCO3 (3 x 15 mL), brine (Ix 20 mL), dried over MgSO4 and concentrated. The residue was washed with he to provide 2-hydrazinyl-4-methyl-l, 8-naphthyridine. Spectroscopic data: 1 H NMR (300 MHz, cdcl3) d ppm 2.56 (s, 3 H) 6.66 (s, 1 H) 7.22 (dd, J = 7.91, 4.40 Hz, 1 H ) 8.11 (dd, J = 8.06, 1.90 Hz, 1 H) 8.82 (dd, 1 H).
N- (3, 5-Dichlorophenyl) -2- (4-methyl-l, 8-naphthyridin-2-yl) hydrazinecarboxamide: to a solution of 2-hydrazinyl-4-methyl-l, 8-naphthyridine, prepared above, (84 mg, 0.482 mmol) in CH2C12 was added 3,5-dichlorophenyl isocyanate (91 mg, 1.0 eq). The resulting mixture was stirred at room temperature overnight. The resulting precipitate was filtered and washed with EtOAc to provide the desired title compound. Spectroscopic data: 1 H NMR (300 MHz, DMSO-d &) d ppm 2.51 (s, 3 H) 6.78 (s, 1 H) 7.05 (t, J = 1, 90 Hz, 1 H) 7.23 (dd, J = 7.91, 4.40 Hz, 1 H) 7.61 (br. S., 2 H) 8.22 (dd, .7 = 8.06, 1.90 Hz, 1 H) 8.57 (br. S., 1 H) 8.68 (dd, J = 4.40, 1.76 Hz, 1 H) 8.98 (s, 1 H) 9.22 (br. s., 1 H). ple 21 Synthesis of N- (3,5-dichlorophenyl) -2- (4-isopropyl-l, 8-naphthyridin-2-yl) hydrazinecarboxamide The title compound was generated from N- (3- isobutyrylpyridin-2-yl) pivalamide according to the chemistry described in Reaction Scheme 1, which was described above. The intermediaries were separated and characterized.
N- (3-Isobutyrylpyridin-2-yl) pivalamide: a solution of N- (pyridin-2-yl) ivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1 eq.) And N-methoxy-N-methylisobutyramide (2.60 g. , 1.1 eq) was reacted as shown in Reaction Scheme 1 to provide 3.10 g (69%) of N- (3-isobutyrylpyridin-2-yl) pivalamide. Spectroscopic data: 1 H NMR (300 MHz, cdcl3) d ppm 1.21 (d, J = 7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt, J- = 13.70 , 6.78 Hz, 1 H) 7.08 (dd, J = 7.91, 4.69 Hz, 1 H) 8.19 (dd, J = 8.20, 2.05 Hz, 1 H) 8 , 63 (dd, J = 4.83, 1.90 Hz, 1 H) 11, 51 (br. S., 1 H). 3 - . 3-hydroxy-4-methyl-3- (2-pivalamidopyridin-3-yl) tere-butyl pentanoate; a solution of IV- (3-isobut iri lpyridin-2-yl) pivalamide (3.10 g, 12.5 mmol), LDA (1.5 M, 17.50 mL, 2.1 eq) and ethyl acetate. -butyl (3.5 mL, 2.1 eq) was reacted as shown in Reaction Scheme 1 to provide 3-hydroxy-4-methyl-3- (2-pivalamidopyridin-3-yl) pentanoate of tere- butyl which was used in the next step without further purification. 4 - . 4-Isopropyl-1, 8-naphthyridin-2 (1H) -one: a solution of 3-hydroxy-4-methyl-3- (2-pivalamidopyridin-3-yl) entanoate of tere-butyl (3.78 g, 10.4 mmol) in 12.0 mL of 3N HCl was reacted as shown in Reaction Scheme 1 to provide 4-isopropyl-l, 8-naphthyridine-2 (lyridyl). ) -one desired (800 mg, 41%). Spectroscopic data: 1H NR (300 MHz, cdcl3) d ppm 1.34 (d, J = 7.03 Hz, 6 H) 3.34 (quin, J = 6.81 Hz, 1 H) 6.66 (s) , 1 H) 7.23 (dd, J = 12.31, 4.10 Hz, 2 H) 8.09 (dd, .7 = 8.06, 1.61 Hz, 1 H) 8.71 (dd) , J = 4.69, 1.47 Hz, 1 H) 11.98 (br. S, 1 H). 2-Chloro-A-isopropyl-1,8-naphthyridine: a solution of 4-isopropyl-1,8-naphthyridin-2 (1-yl) -one (800 mg, 4.3 mmol) and 475 μl of P0C13 in toluene were reacted as shown in Reaction Scheme 1 to provide the desired 2-chloro-4-isopropyl-1, 8-naphthyridine (690 mg, 79%). Spectroscopic data: ""? NMR (300 MHz, cdcl3) d ppm 1.41 (d, J = 6.74 Hz, 6 H) 3.68 (dq, J = 7.03, 6.84 Hz, 1 H) 7.38 (s) , 1 H) 7.52 (dd, J = 8.35, 4.25 Hz, 1 H) 8.44 (dd, J = 8.50, 2.05 Hz, 1 H) 9.09 (dd, 1 HOUR) . 2 - . 2-Hydrazinyl-4-isopropyl-1, 8-naphthyridine: a solution of chloro-4-isopropyl-1,8-naphthyridine (690 mg, 3.4 mmol) in NH 2 NH 2 was reacted as shown in the reaction Scheme 1 above to provide the desired title compound (620 mg, 92%). Spectroscopic data: 1 H NMR (300 MHz, cdcl3) d ppm 1.35 (d, .7 = 6.74 Hz, 6 H) 3.45 - 3.59 (m, 1 H) 6.70 (br. S ., 1 H) 7.21 (dd, J = 8.06, 4.54 Hz, 1 H) 8.19 (d, J = 1, 62 Hz, 1 H) 8, 79 (br. S., 1 H).
N- (3,5-Dichlorophenyl) -2- (4-isopropyl-1,8-naphthyridin-2-yl) hydrazinecarboxamide: a sample of 100 mg (0.5 mmol) of 2-hydrazinyl-4-isopropyl 1 - 1,8-naphthine iridine and 94 mg (1.0 eq) of dichlorophenium 3,5-isocyanate were reacted as shown in Reaction Scheme 1 above to provide the desired title compound. Spectroscopic data: H NMR (300 MHz, DMSO-dg) d ppm 1.23 (d, J = 6.74 Hz, 6 H) 3.56 (d, J = 6.74 Hz, 1 H) 6.82 (s, 1 H) 7.04 (t, J "= l, 76 Hz, 1 H) 7.23 (dd, J = 8.20, 4.40 Hz, 1 H) 7.59 (br. ., 2 H) 8.31 (d, J = 1, 47 Hz, 1 H) 8.54 (br. S., 1 H) 8.66 (d, J = 1, 17 Hz, 1 H) 8 99 (br. S., 1 H) 9.25 (br. S., 1 H).
Example 22 Synthesis of N- (3,5-dichlorophenyl) -2- (4-isopropyl-5,8-dimethylquinolin-2-yl) hydrazinecarboxamide The title compound was generated from 2,5-dimethylaniline in accordance with the chemistry described in the following Reaction Scheme (Reaction Scheme 2). The intermediaries separated and characterized.
Reaction scheme 2 N- (2, 5-Dimethylphenyl) -4-methyl-3-oxopentanamide: a mixture of 2,5-dimethylaniline (7.70 g, 63.54 mmol) and ethyl 4-methyl-3-oxopentanoate (10, 00 g, 1.0 eq) was refluxed at 160 ° C overnight. After the reaction mixture was cooled to room temperature, it was triturated with hexane. The resulting precipitate was filtered and dried under high vacuum to provide the desired N- (2, 5-dimethylphenyl) -4-methyl-3-oxopentanamide. Spectroscopic data: 1 H NMR (300 MHz, cdcl 3) d ppm 1,18 (d, J = 1, 03 Hz, 6 H) 2,30 (d, J = 7,62 Hz, 6 H) 2,66 - 2 , 85 (m, 1 H) 3.64 (s, 2 H) 6.87 (d, J = 8.50 Hz, 1 H) 7.06 (d, J = 7.62 Hz, 1 H) 7 77 (s, 1 H) 9.13 (br. S., 1 H). 4-Isopropyl-5,8-dimethylquinolin-2-ol: a sample of N- (2,5-dimethylphenyl) -4-methyl-3-oxopentanamide and 10.0 mL of H2SO4 was reacted at 100 ° C for 1 hour. hour. After the The reaction was cooled to room temperature, it was quenched in ice-H20. The resulting mixture was extracted with CH2C12 (3 x 20 mL). The combined organic extracts were washed with saturated NaHCO 3 (3 x 15 mL), brine (1x 20 mL), dried over MgSO 4 and concentrated. The residue was recrystallized from EtOAc to provide 1.30 g of the desired 4-isopropyl-5,8-dimethylquinolin-2-ol. Spectroscopic data: 1 H NMR (300 MHz, CDC13) (ppm 1.29 (d, J = 6.45 Hz, 6 H) 2.41 (s, 3 H) 2.77 (s, 3 H) 3.84 (Who, J = 6.59 Hz, 1 H) 6.67 (s, 1 H) 6.93 (d, J = 7.62 Hz, 1 H) 7.19 (d, J = 7.62 Hz , 1 H) 8.81 (br. S., 1 H). 2-Chloro-4-isopropyl-5,8-dimethylquinoline; a solution of 4-isopropyl-5,8-dimethylquinolin-2-ol (1.30 g, 6.05 mmol), 700 L (1.2 eq) of P0C13 in toluene was reacted as shown in the Scheme of reaction 1 above to provide 1.00 g of 2-chloro-4-isopropyl-5,8-dimethylquinoline (71%). Spectroscopic data: XH NMR (300 MHz, cdcl3) d ppm 1.34 (d,, 7 = 6.74 Hz, 6 H) 2.71 (s, 3 H) 2.87 (s, 3 H) 4, 12 (quin,, 7 = 6.74 Hz, 1 H) 7.21 (d, J = 7.33 Hz, 1 H) 7.32 (s, 1 H) 7.40 (d, J = 7, 33 Hz, 1 H). 2 - . 2-Hydrazinyl-4-isopropyl-5,8-dimethylquinoline: a solution of 2-chloro-4-isopropyl-5,8-dimethylquinoline (1.00 g, 4.3 mmol) in NH 2 NH 2 was reacted as described. shown in Reaction Scheme 1 above to provide the title compound. Spectroscopic data: ?? NMR (300 MHz, cdcl3) d ppm 1.30 (d, J = 6.74 Hz, 6 H) 2.64 (s, 3 H) 2.82 (s, 3 H) 3.95 - 4.10 (m, 1 H) 6, 72 (s, 1 H) 6.98 (d, J = 7.33 Hz, 1 H) 7.30 (d, J = 7.33 Hz, 1 H).
N- (3,5-Dichlorophenyl) -2- (4-isopropyl-5,8-dimethylquinolin-2-yl) hydrazinecarboxamide: a solution of 2-hydrazinyl-4-isopropyl-5,8-dimethylquinoline (100 mg, , 44 mmol) and 82 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as shown in Reaction Scheme 1 above to provide the desired title compound. Spectroscopic data: XH NMR (300 MHz, DMS0-d6) d ppm 1.23 (d, J = 6.74 Hz, 6 H) 2.42 (s, 3 H) 2.74 (s, 3 H) 3 , 88-4.06 (m, 1 H) 6.89 (s, 1 H) 6.94 (d, J "= 7.33 Hz, 1 H) 7.07 (t, J = 1, 90 Hz , 1 H) 7.22 (d, J = 7.03 Hz, 1 H) 7.65 (br. S., 2 H) 8.27 (br. S., 1 H) 8.58 (s, 1 H) 9.24 (br. S., 1 H).
Example 23 Synthesis of N- (3,5-dichlorophenyl) -2- (4-isopropylquinolin-2-yl) hydrazinecarboxamide The title compound is generated from aniline in accordance with the chemistry described in Reaction Scheme 1 and Reaction Scheme 2. The intermediaries were separated and characterized. 4-Methyl-3-oxo-N-phenylpentanamide: Aniline (5.80 g, 62.3 mmol) and 10.0 g (1.0 eq.) Of ethyl isobutyryl acetate was reacted as shown in the Scheme of reaction 2, which was described above to provide 6.70 g (52%) of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, cdcl3) d ppm 1.17 (d, .7 = 7.03 Hz, 6 H) 2.64-2.83 (m, 1 H) 3.61 (s, 2 H) 7.11 (t, J = 7.33 Hz, 1 H) 7.32 (t, "7 = 7.91 Hz, 2 H) 7.51-7.59 (m, 2 H) 9, 20 (br. S., 1 H). 4 - . 4-Isopropylquinolin-2-ol: a solution of 4-methyl-3-oxo-N-phenylpentanamide (3.70 g, 18.03 mmol) in 15 mL H2SO4 was reacted as shown in Reaction Scheme 2 above to provide 1.95 g (57%) of the desired title compound. Spectroscopic data: XH NMR (300 MHz, cdcl3) d ppm 1.36 (d, J = 6.74 Hz, 6 H) 3.45 (quin, J = 6.81 Hz, 1 H) 6.67 (s) , 1 H) 7.15-7.32 (m, 1 H) 7.40-7.61 (m, 2 H) 7.79 (d, J = 8.50 Hz, 1 H) 12.28 ( br. s., 1 H). 2 - . 2 - . 2-Chloro-4-isopropylquinoline: 4-Isopropylquinolin-2-ol (1.95 g, 10.43 mmol) and 1.14 mL (1.2 eq) of POCl3 in toluene were reacted as shown in the Scheme of reaction 1 above to provide 1.8 g (84%) of the desired title compound. Spectroscopic data: K NMR (300 MHz, cdcl3) d ppm 1.40 (d, J = 6.74 Hz, 6 H) 3.71 (quin, J = 6.81 Hz, 1 H) 7.28 (s) , 1 H) 7.48-7.63 (m, 1 H) 7.65-7.78 (m, 1 H) 7.98-8.10 (m, 2 H). 2-Hydrazinyl-4-isopropylguinoline: a solution of 2-chloro-4-isopropylquinoline (1.80 g, 8.8 mmol) in H2 H 2 was reacted as shown in Reaction Scheme 1 above to provide the desired compound of the title. Spectroscopic data: H MR (300 MHz, cdcl3) d ppm 1.41 (d, J = 6.74 Hz, 6 H) 3.51 - 3.76 (m, 1 H) 7.20 - 7.35 ( m, 1 H) 7.44-7.60 (m, 2 H) 7.61-7.79 (m, 1 H) 7.84-8.06 (m, 1 H).
N- (3, 5-Dichlorophenyl) -2- (4-isopropylolquinol ind 2-yl) hydrazinecarboxamide: a solution of 2-hydrazinyl-4-isopropylquinoline (97 mg, 0.48 mmol) and 91 mg (1, 0 eq) of 3,5-dichlorofenyl isocyanate was reacted as shown in Reaction Scheme 1 above to provide the desired title compound. Spectroscopic data: XH NMR (300 MHz, DMSO-d6) d ppm 1.29 (d, J "= 6.74 Hz, 6 H) 3.53 - 3.71 (m, 1 H) 6.83 (s , 1 H) 7.09 (t, J "= 1, 90 Hz, 1 H) 7.28 (td, J = 7.47, 1.46 Hz, 1 H) 7.45-7.62 (m , 2 H) 7.69 (br. S., 2 H) 7.94 (d, J = 7.62 Hz, 1 H) 8.50 (br. S., 1 H) 8.70 (s, 1 H) 9.23 (br. S., 1 H).
Example 24 Synthesis of N- (2, 6-di c loropi-ridin-4-i 1) - 2 - (4,8-dimeti 1 -quinol-2-yl) hydrazinecarboxamide The title compound was generated from 2-chloro-4,8-dimethylquinoline in accordance with the chemistry described in Reaction Scheme 1 and Reaction Scheme 2. Intermediates were separated and characterized. 2-Hydra zini 1 - 4, 8 - dimet i lquinol ina: a solution of 2-chloro-4,8-dimet i lquinol ina (1.00 g, 5.2 mmol) in NH 2 NH 2 was reacted as shown in Reaction Scheme 1 above to provide the desired title compound that was used in the next step without further purification.
N- (2,6-Dichloropyridin-4-yl) -2- (4,8-dimet i lquinol in-2-yl) hydrazinecarboxamide: a solution of 2-hydra z ini 1 - 4, 8 - dimet i 1 quinol ina (110 mg, 0.60 mmol) and 111 mg (1.0 eq) of 2,6-di chloro-4-isocyanatopyridine was reacted as shown in Reaction Scheme 1 above to provide the desired compound of Title. Spectroscopic data: XH NMR (300 MHz, DMSO-d6) d ppm 2.50 (s, 3 H) 2.56 (s, 3 H) 6.79 (s, 1 H) 7.18 (t, J) "= 7.62 Hz, 1 H) 7.41 (d, J" = 7.03 Hz, 1 H) 7.70 (d, J = 8, 20 Hz, 2 H) 8.72 (s, 2 H).
Example 25 Synthesis of N- (3,5-dichlorophenyl) -2- (4,8-dimethylquinolin-2-yl) hydrazinecarboxamide The title compound was generated from 2-hydrazinyl-4,8-dimethylquinoline in accordance with the chemistry described in Reaction Scheme 1. The Intermediate 2-hydrazinyl-4,8-dimethylquinoline was prepared in accordance with the Scheme of reaction 1 and its characterization was presented previously (see above).
N- (3,5-Dichlorophenyl) -2- (4,8-dimethylquinol in-2-yl) hydrazinecarboxamide: a solution of 2-hydrazinyl -4,8-dimethylquinoline (100 mg, 0.53 mmol) and 100 mg (1.0 eq) of 1,3-dichloro-5-isocyanatobenzene was reacted as shown in Reaction Scheme 1 above to provide the desired title compound. Spectroscopic data: 1 H NMR (300 MHz, DMS0-d6) d ppm 2.51 (s, 3 H) 2.55 (s, 3 H) 6.77 - 6.80 (m, 1 H) 7.09 ( t, J = 1, 76 Hz, 1 H) 7.17 (dd, .7 = 8.20, 7.03 Hz, 1 H) 7.40 (d, J = 6.74 Hz, 1 H) 7 , 65-7.72 (m, 3 H) 8.40 (br. S., 1 H) 8.62 (s, 1 H) 9.25 (br. S., 1 H).
Example 26 Synthesis of N- (2,6-dichloropyridin-4-yl) -2- (4-methylquinolin-2-yl) hydrazinecarboxamide The title compound was generated from commercially available 2-chloro-4-methylquinoline in accordance with the chemical procedure described above in Reaction Scheme 1. The intermediate 2-hydrazinyl-methylquinoline was used in the next step without purification additional. 2 - . 2-Hydrazinyl -4-methylquinoline: a solution of 2-chloro-4-methylquinoline (1.00 g, 5.63 mmol) in NH2NH2 was reacted as shown in Reaction Scheme 1 above to provide the title compound which was used in the next step without further purification.
N- (2,6 -Dichloropyridin-4-yl) -2- (4-methylquinolin-2-yl) hydrazinecarboxamide: a solution of 2-hydrazinyl-4-methylquinoline (100 mg, 0.58 mmol) and 110 mg ( 1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted as shown in Reaction Scheme 1 above to provide the desired title compound. Spectroscopic data: XH NMR (300 MHz, DMSO-d6) d ppm 2.57 (s, 3 H) 6.80 (s, 1 H) 7.30 (t, J = 7.47 Hz, 1 H) 7.50-7.64 (m, 2 H) 7.87 (d, J = 8, 20 Hz, 1 H) 8.78 (s, 1 H) 8.91 (br. S., 1 H).
Example 27 Synthesis of N- (3,5-dichlorophenyl) -2- (4,5, 8-trimethylquinolin-2-yl) hydrazinecarboxamide The title compound was generated from 2,5-dimethylaniline in accordance with the chemical procedure described in Reaction Scheme 1 and Reaction Scheme 3 below. The intermediaries were separated and characterized.
Reaction scheme 3 N- (2, 5-Dimethylphenyl) -3-oxobutanamide: a mixture of 2,5-dimethylaniline (1.00 g, 8.25 mmol) and ethyl 3-oxobutanoate (1.0 mL, 1.0 eq) was microwaved at 180 ° C for 5 minutes. After the reaction mixture was cooled to room temperature, it was triturated with hexane. The resulting precipitate was filtered and dried under high vacuum to provide the desired title compound. Spectroscopic data: 1 H NMR (300 MHz, cdcl3) d ppm 2.28 (s, 3 H) 2.32 (s, 3 H) 2.34 (s, 3 H) 3.63 (s, 2 H) 6 , 88 (d, J = 7.62 Hz, 1 H) 7.07 (d, J = 7.62 Hz, 1 H) 7.75 (s, 1 H) 9.00 - 9.12 (m, 1 HOUR) . , 5, 8-trimethylquinolin-2-ol: a sample of 5.50 g (26.8 mmol) of N- (2,5-dimethylphenyl) -3-oxobutanamide in 10.0 mL of H2SO4 was microwaved at 140 ° C for 5 minutes. After the reaction was cooled to room temperature, it was quenched in ice-H20. The resulting mixture was basified with saturated NaHCO 3. The resulting mixture was extracted with CH2C12 (3 x 20 mL) and the combined organic extracts were washed with H20 (1 x 15 mL), brine (Ix 20 mL), dried over MgSO4 and concentrated to provide the desired title compound (1.4 g, 28%). Spectroscopic data: XH NMR (300 MHz, cdcl3) d ppm 2.41 (s, 3 H) 2.69 (d, J = 1, 17 Hz, 3 H) 2.73 (s, 3 H) 6.48 (s, 1 H) 6.90 (d, J = 7.33 Hz, 1 H) 7.19 (d, .7 = 7.62 Hz, 1 H) 8.87 (br. s., 1 H ). 2-Chloro-4,5,8-trimethylquinoline: a solution of 4,5,8-trimethylquinolin-2-ol (2.40 g, 12.8 mmol) and 1.4 mL (1.2 eq) of POCI3 in toluene was reacted as shown in Reaction Scheme 1 above to provide the desired title compound (2.2 g, 85%). Spectroscopic data: 1 H NMR (300 MHz, cdcl3) d ppm 2.68 (s, 3 H) 2.82 (s, 3 H) 2.85 (s, 3 H) 7.12 (s, 1 H) 7 , 18 (d, J = 7.33 Hz, 1 H) 7.39 (d, 1 H). 2-Hydrazinyl-4,5,8-trimethylquinoline: a solution of 2-chloro-4,5,8-trimethylquinoline (2.2 g, 10.7 mmol) in NH 2 NH 2 was reacted as shown in the reaction Scheme 1 above to provide the desired title compound (830 mg, 38%). Spectroscopic data: 1 H NMR (300 MHz, cdcl3) 6 ppm 2.62 (s, 3 H) 2.78 (s, 6 H) 4.13 (br. S., 2 H) 5.74 (br. S ., 1 H) 6.52 (s, 1 H) 6.95 (d, J = 7.03 Hz, 1 H) 7.28 (d, 1 H).
N- (3,5-Dichlorophenyl) -2- (4, 5, 8-trimethylquinolin-2-yl) hydrazinecarboxamide: a solution of 2-hydrazinyl-4,5,8-trimethylquinoline (100 mg, 0.50 mmol) and 93.53 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as shown in Reaction Scheme 1 above to provide the desired title compound. Spectroscopic data: XH NMR (300 MHz, DMS0-ds) d ppm 2.43 (s, 3 H) 2.73 (s, 3 H) 2.77 (s, 3 H) 6.69 (s, 1 H ) 6.92 (d, J = 7.03 Hz, 1 H) 7.09 (t, J = 1, 90 Hz, 1 H) 7.23 (d, .7 = 7.62 Hz, 1 H) 7.68 (br. S., 2 H) 8.35 (s, 1 H) 8.53 (s, 1 H) 9.24 (br. S., 1 H).
TABLE 2 25 As can be seen in the above results, the pyrazolopyridinyl compounds of the present invention are preferred over the benzopyridinyl or pyrido compounds pyridinyl. In particular, pyrazolopyridinyl compounds comprising substituted aryl which is pyridinyl are especially preferred. And finally, pyrazolopyridinyl compounds comprising substituted aryl which is pyridinyl and where the substitution pattern is o-halo, o-alkyloxy, more preferably o-chloro, o-ethyloxy, propyloxy or butyloxy are more preferred.
As a result of the above activity of the compounds used in the method of the present invention, it is clear that such compounds can be used in the treatment and / or prevention of the following diseases and conditions of the eye as well as of other diseases and conditions discussed below . (It should be noted that "treating" means mitigating and / or modulating a disease or disorder that exists in a subject (whether the subject is aware of the disease or disorder, or not) or delaying the onset of the disease or disorder and the means "preventatives" that prevent the recurrence, onset or development of one or more symptoms of the disease or disorder in a subject by administration of one or more compounds of the invention).
Eye diseases; Wet and dry macular degeneration associated with age, diabetic retinopathy, retinopathy of prematurity, geographic atrophy, glaucomatous optic neuropathy.
Systemic diseases related to the vascular barrier; various inflammatory diseases; including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edema, and ventilation-induced lung injury.
Allergies and other inflammatory diseases; urticaria, bronchial asthma and other diseases of the respiratory tract including diseases of pulmonary emphysema and chronic obstructive pulmonary.
Heart protection; ischemia / reperfusion injury, atherosclerosis.
Anti-fibrosis; ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced corneal fibrosis, conjunctiva and Tenon's capsule.
Pain and anti-inflammation; acute pain, outburst of chronic pain, musculoskeletal pain, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic pain in knees and joints, tendinitis, osteoarthritis, bursitis, neuropathic pain.
Healing of wounds; healing without scars of wounds of aesthetic skin surgery and eye surgery, GI surgery, surgery in general, various mechanical and heat injuries.
See, for example, the following articles: 1. Hla, Timothy "Inhibitor of the Receptor Activity of the S1P2 Receptor for Inhibiting Pathological Angiogenesis in the eye. "PCT Int. Appl. (2008), 54 pp. WO 2008154470 To the 2. Athanasia Skoura, Teresa Sanchez, Kevin Claffey, Suzanne M. Mandala, Richard L. Proia, and Timothy Hla "Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina." J Clin Invest. 2007 September 4; 117 (9): 2506-2516. 3. Serriere-Lanneau V, Teixeira-Clerc F, Li L, et al. The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing. FASEB J 2007 21: 2005-13.
The foregoing description details the specific methods and compositions that may be employed to practice the present invention and represents the best form contemplated. Therefore, regardless of how detailed it may appear in the text, it should not be construed as limiting the general scope of the present, - on the contrary, the scope of the present invention should be governed solely by the legitimate construction of the appended claims. In particular, the present invention includes, as new preferred compounds, which exhibit subtypes of selective modulator activity of sphingosine-l-phosphate-2 (SIP2) receptors, the compounds which are selected from the group consisting of 1- (2-chloro) -6-pyridine of lower alkyloxy-4-yl) -3- ((7-isopropyl-3, 3- dimethyl-lH-pyrazolo [4, 3-jb] pyridin-5-yl) methyl) ureas and l- (2-chloro-6-lower alkyloxy pyridin-4-yl) -3- ((7-isopropyl-1, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) imino) ureas.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (11)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:
1. The compounds represented by formula I which have biological activity of the sphingosine-1-phosphate receptor antagonist: characterized because: A is a direct bond or (CR) and B, C and D are independently selected from the group consisting of (CR) and N, where R is H or alkyl; provided, however, that not all B, C and D are N and, when A is a direct link, D is (CR). R3 is selected from the group consisting of alkyl: X is selected from the group consisting of 0, NR4 and CRR5, where R4 and R5 are independently selected from the group consisting of H and alkyl, And it is selected from the group consisting of 0 or S and Z is a substituted aryl ring.
2. A compound represented by formula II, a pharmaceutically acceptable salt thereof characterized in that y are independently selected from the group consisting of H and alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; R3 is independently selected from the group consisting of alkyl, methoxy, hydroxyl, halogen, nitrile and trifluororaethyl; D is CR or N; R is H or alkyl, -X is 0, NR4 or CR4R5, where R4 and R5 are independently selected from the group consisting of H and alkyl, for example, lower alkyl and may have from 1 to 10 carbons and may be cyclic or branched chain having 3 to 10 carbons; methoxy, hydroxyl, F, Br, I, nitrile and trifluoromethyl; And it's O or S, Z is a substituted aryl ring, having the following structure: where R6 and R7 are independently selected from the group consisting of alkyl and may include from 1 to 10 carbons and can be cyclic or branched chain alkyls having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl; Y E is N or CR.
3. The compound according to claim 2, characterized in that R1, R2 and R3 are independently H, halogen, methyl or isopropyl; X is NR4; R4 is H; And it is 0; R6 and R7 are independently H or chloro; E is N or CR; Y R is H.
4. The compound according to claim 2, characterized in that the compound is selected from the group consisting of N- (3,5-dichlorophenyl) -2- (4-methyl-l, 8-naphthyridin-2-yl) hydrazinecarboxamide, N- (3,5-dichlorophenyl) -2- (4-isopropyl-l, 8-naphthyridin-2-yl) hydrazinecarboxamide, N- (3,5-dichlorophenyl) -2- (4-isopropyl-5,8-dimethylquinolin-2-yl) hydrazinecarboxamide, N- (3,5-dichlorophenyl) -2- (4-isopropylquinolin-2-yl) hydrazinecarboxamide, N- (2,6-dichloropyridin-4-yl) -2- (4,8-dimethylquinolin-2-yl) hydrazinecarboxamide, N- (3,5-dichlorophenyl) -2- (4,8-dimethylquinolin-2-yl) hydrazinecarboxamide, N- (2,6-dichloropyridin-4-yl) -2- (4-methylquinolin-2-yl) hydrazinecarboxamide and N- (3,5-dichlorophenyl) -2- (4, 5, 8-trimethylquinolin-2-yl) hydrazinecarboxamide
5. The compound represented by formula III, or a pharmaceutically acceptable salt thereof: characterized in that R1 and R2 are independently selected from the group consisting of H and alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; R3 is independently selected from the group consisting of alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; X is O, NR 4, CRR 5, where R 4 and R 5 are independently selected from the group consisting of H and alkyl, for example, lower alkyl, and may have from 1 to 10 carbons and may be cyclic or branched chain alkyls having 3 to 10 carbon atoms. at 10 carbons; methoxy, hydroxyl, F, Br, I, nitrile and trifluoromethyl; And it is O or S; R is H, methoxy or alkyl Z is a substituted aryl ring, having the following structure: wherein R6 and R7 are independently selected from the group consisting of alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyls having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; Y E is N or CR.
6. The compound according to claim 5, characterized in that R1, R2 and R3 are independently methyl or isopropyl; X is NR4 or CR4R5; R4 is H; R5 is H; Cast; R6 and R7 are independently selected from the group consisting of alkyl and may include from 1 to 5 carbons, methoxy, ethoxy, chloro and trifluoromethyl; E is N or CR; Y R is H or methoxy.
7. The compound according to claim 5, wherein the compound is selected from the group consisting of N- (3,5-dichlorophenyl) -2- (7-isopropyl-1,3-dimethyl-1H-pyrazolo [4, 3-jb] pyridin-5-yl) hydrazinecarboxamide, 1- (2,6-dichloropyridin-4-yl) -3- ((7-isopropyl-l, 3-dimethyl-lH-irazolo [4, 3-b] iridin-5-yl) methyl) urea, N- (2-Butyl-6-chloropyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-yl] pyridin-5-yl) hydrazinecarboxamide, N - (2-Chloro-6-ethoxypyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-l-pyrazolo [4, 3-± >] pyridin-5-yl) hydrazinecarboxamide, 1- (3,5-dichlorophenyl) -3- ((1, 3, 7-trimethyl-lH-pyrazolo [4, 3-jb] pyridin-5-yl) methyl) urea, N- (2,6-dichloropyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-jb] pyridin-5-yl) hydrazinecarboxamide, N- (3,5-bis (trifluoromethyl) phenyl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-Jb] pyridin-5-yl) hydrazinecarboxamide, N- (3-chloro-5-methoxypyridin-4-yl) -2- (7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide, 1- ( 2,6-dichlorophenyl) -3- ((7-isopropyl-1,3-dimethyl-1-pyrazolo [4,3-jb] pyridin-5-yl) methyl) urea, 1- (2-chloro-6-methoxypyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-l-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea, N- (2-chloro-6-propylpyridin-4-yl) -2- (7- isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-jb] pyridin-5-yl) hydrazinecarboxamide, 1- (2-Chloro-6-propylpyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea, - (2-chloro-6-ethoxypyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea, 1- (2-Chloro-6-propoxypyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) rea, N- (2-chloro-6-propoxypyridin-4-yl) -2- (7-isopropyl-l, 3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide, N- (2-Butoxy-6-chloropyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide, 1- (2-Butoxy-6-chloropyridin-4-yl) -3- ((7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] pyridin-5-yl) methyl) urea, N- (2-ethoxypyridin-4-yl) -2- (7-isopropyl-1,3-dimethyl-1-pyrazolo [4, 3-b] pyridin-5-yl) hydrazinecarboxamide and N- (5-Chloro-2,4-dimethoxyphenyl) -2- (7-isopropyl-1,3-dimethyl-lH-pyrazolo [4, 3-b] iridin-5-yl) hydrazinecarboxamide.
8. Use of a compound according to claim 2, represented by general formula II: wherein 1 and R2 are independently selected from the group consisting of H and alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; R3 is independently selected from the group it consists of alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; D is CR or N; R is H or alkyl; X is 0, NR4 or CR4R5, where R4 and R5 are independently selected from the group consisting of H and alkyl, for example, lower alkyl and may have from 1 to 10 carbons and may be cyclic or branched chain alkyls having 3 or more carbon atoms; at 10 carbons; methoxy, hydroxyl, F, Br, I, nitrile and trifluoromethyl; And it's O or S, Z is a substituted aryl ring, having the following structure: wherein R6 and R7 are independently selected from the group consisting of alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyls having from 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl; Y E is N or CR, in the preparation of a medicament for treating a disease of a mammal that is selected from the group consisting of eye diseases; systemic diseases related to the vascular barrier; allergies and other inflammatory diseases; diseases or heart conditions; fibrosis; pain and wounds.
9. A pharmaceutical composition useful for treating or preventing diseases and conditions that are selected from the group consisting of ocular diseases; systemic diseases related to the vascular barrier; allergies and other inflammatory diseases; diseases or heart conditions; fibrosis;. pain and wounds characterized in that it comprises a compound according to claim 2 in combination with a pharmaceutically acceptable carrier.
10. Use of a compound according to claim 9 represented by general formula III: wherein R1 and R2 are independently selected from the group consisting of H and alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; R3 is independently selected from the group consisting of alkyl, methoxy, hydroxyl, halogen, nitrile and trifluoromethyl; X is 0, NR4 or CR4R5, where R4 and R5 are independently selected from the group consisting of H and alkyl, for example, lower alkyl and can have from 1 to 10 carbons and can be cyclic or branched chain alkyls having from 3 to 10 carbons; methoxy, hydroxyl, F, Br, I, nitrile and trifluoromethyl; And it is O or S; R is H, methoxy or alkyl; Z is a substituted aryl ring, having the following structure: wherein R6 and R7 are independently selected from the group consisting of alkyl and may include from 1 to 10 carbons and may be cyclic or branched chain alkyls having from 3 to 10 carbons; methoxy, ethoxy, hydroxyl, halogen, nitrile and trifluoromethyl; Y E is N or CR, for making a medicament for treating a disease of a mammal that is selected from the group consisting of eye diseases; systemic diseases related to the vascular barrier; allergies and other inflammatory diseases; diseases or heart conditions; fibrosis; pain and wounds.
11. A pharmaceutical composition useful for treating or preventing diseases and conditions selected from group consisting of eye diseases; systemic diseases related to the vascular barrier; allergies and other inflammatory diseases; diseases or heart conditions; fibrosis; pain and wounds characterized in that it comprises a compound according to claim 5 in combination with a pharmaceutically acceptable carrier.
MX2012003718A 2009-09-29 2010-09-28 Condensed ring pyridine compounds as subtype-selective modulators of sphingosine-1-phosphate-2 (s1p2) receptors. MX2012003718A (en)

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